The career development goal of this proposal is to complement my background in mathematical and computational modeling by receiving training in and gaining experience in the cell and molecular biological aspects of alcohol research, specifically in applications involving cell signaling by reactive oxygen species (ROS)- and tumor necrosis factor (TNF)-a that control cell death and survival. These signaling pathways play key roles in tissue injury and are strongly affected by excessive chronic alcohol consumption. My current skills include development and analysis of mathematical models, systems of ordinary differential equations (ODE), describing complex biological networks and membrane-transport systems with different regulatory loops. I have experience in studying such nonlinear phenomena in ODE as hysteresis, multi-stability and threshold effects as well as auto-oscillations and resonance. In my previous modeling studies of cell signaling networks, I demonstrated the potential for hysteresis, bistability and threshold phenomena in mitogen activated protein kinase (MARK) activation as a result of multi-site (de)phosphorylation in the MARK cascade My entry into the field of the alcohol research will be supervised by my mentor Dr. Jan B. Hoek and my co-mentor Dr. John G. Pastorino, both recognized specialists in alcohol-related cell injury. The training goals of this proposal are a) to obtain more in-depth knowledge of cell and molecular biology, b) to gain experience in current concepts of alcohol-related injury, c) to become familiar with advanced computational methods and experimental approaches that will enable me to conduct quantitative research of apoptosisrelated signaling pathways. This training will consist of taking advanced courses in Cell and Molecular Biology and the biology of alcoholism, and workshops to become familiar with relevant modern experimental approaches. The main research goals of this proposal are to develop quantitative computational models of the control of apoptotic processes that are enhanced by alcohol treatment, resulting in alcohol-induced injury. The research will involve two Specific Aims: 1) To develop a computational model that can provide a quantitative analysis of ethanol-induced alterations in the mitochondria! changes associated with the onset of apoptosis, and 2) To develop a computational model of TNFa-dependent pro- and anti-apoptotic signaling processes that are affected by chronic alcohol treatment, resulting in enhanced susceptibility to cell death. [unreadable] [unreadable] [unreadable]